This application seeks support for a project of research directed toward better understanding of the molecular mechanisms and cellular functions of ion transport across human red blood cell membranes. Our investigation of the molecular mechanism and cellular functions of ion transport seeks to solve four major unsolved problems: First, the mechanisms for the control of chloride-bicarbonate exchange by intra cellular enzymes and hemoglobin including the mediation of these controls by changes in intracellular metabolites and cellular oxygen tension; second, the mechanism by which monovalent cation and a divalent anion are complexed to the anion exchange mechanism for co-transport; third, the kinetics and stoichiometry of active calcium transport in inside-out vesicles; and fourth, the mechanism by which intracellular calcium inhibits the anion exchange mechanism. Experiments are designed to answer questions relevant to these problems for chloride bicarbonate exchange, ion pair transport, and active calcium transport. They involve observations under various conditions of net and tracer fluxes of inorganic anions, alkali and alkaline earth metal cations across red blood cells, red cell ghosts, and inside-out vesicles from red cell membranes. These include measurements after the binding of organic inhibitors, glycolytic enzymes, or hemoglobin to the anion exchange mechanism and after perturbation of membrane lipid composition.